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Method for preparing flupirtine maleate by one-pot method

A technology of flupirtine maleate and fluorobenzylaminopyridine, which is applied in the field of medicine and chemical industry, can solve the problems of easy oxidation and discoloration of fluorobenzylaminopyridine and flupirtine, achieve improved yield, product purity, and convenient operation , The effect of simple process route

Active Publication Date: 2015-07-22
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to provide a preparation method of flupirtine maleate, realize the "one pot" synthesis, and avoid the intermediate 2,3-diamino-6-p-fluorobenzylaminopyridine caused by step-by-step processing And flupirtine is easy to oxidize and change color, overcome the cumbersome operations such as high-pressure hydrogenation in the existing process, reduce production costs, improve product quality and yield, and are suitable for industrial production

Method used

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  • Method for preparing flupirtine maleate by one-pot method
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  • Method for preparing flupirtine maleate by one-pot method

Examples

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Effect test

Embodiment 1

[0027] Put 4Kg of 2-amino-3-nitro-6-chloropyridine, 4Kg of ethylenediamine, and 40L of isopropanol into the reactor, start stirring and heat to reflux; add 3.6Kg of p-fluorobenzylamine into the reactor, The reaction was carried out under reflux for 3 hours. After the heating was stopped, 40 L of purified water was added to the reaction solution, a large amount of yellow solid precipitated and filtered, and the obtained wet product was kept in the reaction kettle. Add 1.2Kg Raney nickel and 40L isopropanol to the reaction kettle, start stirring and heat to reflux, drop 8Kg80% hydrazine hydrate, reflux reaction for 2 hours, after the reaction is complete, drop to room temperature under nitrogen protection, quickly add 4Kg chloroformic acid Ethyl ester was reacted at room temperature for 3 hours. Add 3.2Kg concentrated ammonia water, free for 1 hour, filter, add the filtrate to 6Kg / 120L maleic acid isopropanol solution, cool down and crystallize to obtain off-white solid, blow d...

Embodiment 2

[0029] Put 4Kg of 2-amino-3-nitro-6-chloropyridine, 3Kg of triethylamine, and 50L of absolute ethanol into the reaction kettle, start stirring and heat to reflux; add 4Kg of p-fluorobenzylamine into the reaction kettle, and reflux reaction conditions for 2 hours. After the heating was stopped, 50 L of purified water was added to the reaction solution, a large amount of yellow solid precipitated and filtered, and the obtained wet product was kept in the reaction kettle. Add 1Kg Raney nickel and 50L absolute ethanol to the reaction kettle, start stirring and heat to reflux, add 8.8Kg80% hydrazine hydrate dropwise, reflux reaction for 2 hours, after the reaction is complete, drop to room temperature under nitrogen protection, and quickly add 4.5Kg chlorine Ethyl formate was reacted at room temperature for 2 hours. Add 3Kg triethylamine, free for 1 hour, filter, add the filtrate to 6Kg / 180L maleic acid ethanol solution, cool down and crystallize to obtain off-white solid, blow dr...

Embodiment 3

[0031] Put 4Kg of 2-amino-3-nitro-6-chloropyridine, 3Kg of pyridine, and 20L of methanol into the reactor, start stirring and heat to reflux; add 4.4Kg of p-fluorobenzylamine into the reactor, and react under reflux conditions 4 hours. After the heating was stopped, 20 L of purified water was added to the reaction solution, a large amount of yellow solid precipitated and filtered, and the obtained wet product was kept in the reaction kettle. Add 500g of Raney nickel and 20L of methanol to the reaction kettle, start stirring and heat to reflux, dropwise add 7Kg80% hydrazine hydrate, reflux reaction for 4 hours, after the reaction is complete, drop to room temperature under nitrogen protection, quickly add 3.6Kg ethyl chloroformate , reacted at room temperature for 3 hours. Add 3.6Kg concentrated ammonia water, free for 2 hours, filter, add the filtrate to 5Kg / 50L maleic acid methanol solution, cool down and crystallize to obtain off-white solid, blow dry at 60°C, net weight 7....

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Abstract

The invention discloses a method for preparing flupirtine maleate by a one-pot method. The method is characterized in that 2-amino-3-nitro-6-pyridine and 4-fluorobenzylamine serve as starting materials, and condensation, raney nickel reduction, ethyl chloroformate acylation and maleic acid salification are accomplished in a reactor without intermediate separation. The total yield of flupirtine maleate is increased from below 40% of a step-by-step method to above 70%, and the purity of a crude product is greater than 99%. According to the method, the technical flow is shortened, equipment is decreased, and the problem of high oxidation stain possibility of aminopyridine intermediates in a separation process is effectively solved. The feasibility and controllability of the one-pot method is proven by small-scale and pilot-scale studies, and the method is a handleable and environment-friendly manner to prepare flupirtine maleate, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new process for preparing flupirtine maleate by a "one-pot method". Background technique [0002] Flupirtine maleate is one of 2,3,6-triaminopyridine derivatives, its chemical name is 2-amino-6-[((4-fluorophenyl)methyl)amino]pyridine-3-amino Ethyl formate maleate. Its structural formula is: [0003] [0004] As a moderate-strength non-opioid central analgesic, flupirtine maleate is not addictive to opioid analgesics, and has no inhibitory effect on the respiratory and cardiovascular systems; it also has good tolerance and low neurotoxicity. Toxicity, protection of nerves and lymphocytes and other characteristics. It can be used for the treatment of various types of moderate acute pain, such as acute pain caused by various disorganized pain, surgery, and trauma. It is also very effective for chronic pain and cancer pain, showing a good clinical app...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75C07C51/41C07C57/145
Inventor 吴舰许建良柴雨柱徐丹杨治旻田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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